Diabetes is a major public health problem currently affecting over 24 million individuals in the United States. Type 2 diabetes (T2D) is the main culprit, making up 90-95% of all diabetes cases. As a complex disease, disease risk comes from a combination of lifestyle, environmental, and genetic factors. Previous genetic research has mainly focused on searching for common genetic variants which contribute risk, however, these have only managed to explain ~10% of genetic risk. The "missing heritability" may be due to other factors such as rare variants. The proposed study seeks to explore the role of rare variants in complex diseases, specifically insulin resistance and T2D by using a family based approach to identify rare variants. Insulin resistance is a primary feature of T2D, yet is poorly understood at the genetic level. This project builds upon a highly successful initial study and uses sequence analysis and genotyping methods to identify and confirm variants in target families with extreme phenotypes. Initially this method will be tested using two complementary approaches, examination of a candidate gene phosphotyrosine phosphatase 1B (PTPN1), and evaluation of a previously identified region on chromosome 5 with evidence of linkage to insulin sensitivity. This will be followed by a more generalized survey of the genome for other regions linked to insulin sensitivity. In addition, exome sequencing will be evaluated as a way of searching for variants in a more efficient manner. Finally, variants identified will be assessed for their contribution to insulin sensitivity and T2D disease risk in multiple study populations. This proposal will implement a novel discovery method for rare variants and evaluate the contribution of rare variants in complex diseases. Previously, rare variants have not been well studied in complex diseases due to their low frequency in populations which have made them difficult to detect. This project seeks to develop a cost and time efficient means for the identification of rare variants, which has potentially major implications in complex disease risk, such as diabetes susceptibility. PUBLIC HEALTH RELEVANCE: The goal of this project is to explore a new discovery method for rare genetic variants that contribute to type 2 diabetes disease susceptibility. This knowledge will identify novel variants which will elucidate undiscovered disease mechanisms, allow for early intervention for individuals at risk, and aid in the development of novel therapeutics for prevention and treatment of this disease.